1. Field of the Invention
This invention relates to a process for preparing 5-aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylates of formula I ##STR2## from 2-halopyrroles. Hydrolysis and .beta.-decarboxylation of the compounds of formula I affords ketorolac and related compounds.
2. Background of the Invention
5-Aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids of formula II, and the pharmaceutically acceptable salts and esters thereof, are now under study ##STR3## as analgesic, anti-inflammatory, and anti-pyretic agents for mammals, including man. They are also smooth muscle relaxants. Two exemplary compounds under clinical study in man are ketorolac, 5-benzoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid, (II, Ar=C.sub.6 H.sub.5), and anirolac, 5-p-anisoyl-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylic acid, (II, Ar=p--CH.sub.3 O--C.sub.6 H.sub.5), both disclosed in U.S. Pat. No. 4,089,969 (Muchowski et al., assigned to Syntex (U.S.A.) Inc.). Other compounds, where the 5-aroyl substituents are substituted or unsubstituted benzoyl, furoyl, thenoyl, and pyrroyl, and where the 6- and/or 7-position on the pyrrolo-pyrrole nucleus is optionally substituted by lower alkyl or halogen, and uses thereof, are also disclosed in a series of patents assigned to Syntex (U.S.A.) Inc., beginning with U.S. Pat. No. 4,089,969, including U.S. Pat. Nos. 4,087,539; 4,097,579; 4,140,698; 4,232,038; 4,344,943; 4,347,186; 4,458,081; 4,347,187; 4,454,326; 4,347,185; 4,505,927; 4,456,759; 4,353,829; 4,397,862; 4,457,941; and 4,454,151. U.S. Pat. Nos. 4,511,724 and 4,536,512, assigned to Merck & Co., Inc., disclose 5-(substituted pyrrol-2-oyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid derivatives and 5-(1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-2-oyl)-1,2-dihydro-3H-pyrrolo[1,2-a ]pyrrole-1-carboxylic acid derivatives, respectively.
Various methods for the preparation of these pyrrolo-pyrroles are exemplified in the patent and chemical literature.
For example, U.S. Pat. Nos. 4,347,186; 4,458,081; 4,347,187; and 4,454,326 disclose the preparation of 5-aroyl-pyrrolo-pyrroles from pyrroles, and certain intermediates, by the following route: ##STR4## wherein:
R.sup.1 and X are independently hydrogen or lower alkyl; and
Ar is a moiety selected from the group consisting of ##STR5## in which:
R.sup.2 is hydrogen, methyl, chloro, or bromo, the R.sup.2 substitution being at the 3-, 4- or 5-position of the ring;
R.sup.3 is hydrogen, lower alkyl, lower alkoxycarboxyl, lower alkoxycarbonyl, lower alkylcarbonyl, fluoro, chloro or bromo, the R.sup.3 substitution being at any available position in the ring;
R.sup.4 is hydrogen or lower alkyl; and
Y is oxygen or sulfur.
Because this process introduces the leaving group (--SO.sub.2 CH.sub.3) in a latent form (--SCH.sub.3), an oxidation is required at some point in the process. Therefore, this process is not applicable to the synthesis of compounds containing functionalities, e.g. the --SR group, which are sensitive to the oxidation conditions. Thus, for example, 5-(4-methylthiobenzoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid could not be prepared by this process.
U.S. Pat. Nos. 4,347,185; 4,505,927; and 4,456,759 disclose the preparation of 5-aroyl-pyrrolo-pyrroles from pyrroles, and certain intermediates, by the following route: ##STR6## wherein:
R.sup.5 is hydrogen or lower alkyl;
R.sup.6 is lower alkyl;
X is hydrogen, lower alkyl, lower alkoxyl, lower alkoxycarbonyl, carboxyl, lower alkylcarbonyl, sulfonic acid, sulfonic acid alkyl ester, fluoro, chloro, or bromo; and
Y is chloro or bromo.
Because this process, when used to produce 7-unsubstituted-pyrrolo-pyrroles, requires removal of the 7-halogen by catalytic hydrogenation, it is not applicable to the synthesis of compounds containing functionalities, e.g. --Cl, --Br, --NO.sub.2, --CH.dbd.CH.sub.2, --CH.tbd.CH, which are sensitive to the hydrogenation conditions. Thus, for example, neither 5-(4-chlorobenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid nor 5-(4-vinylbenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid could be prepared by this process.